Project Summary/Abstract The central objectives of this application are: (a) to develop new, reliable, and efficient, methodologies that enable the construction of stereochemically rich scaffolds and (b) to achieve the concise chemical syntheses of naturally occurring small molecules that possess intricate chemical structures. The synthesis of complex small molecules continues to be a vital area of research. In fact, most medicinal agents on the market are prepared by organic synthesis, including the large majority of all new drugs that have become available over the past three decades. Additionally, it should be emphasized that natural products serve as valuable leads for the ultimate discovery of new medicines, in addition to inspiration for the development of new synthetic strategies and methods. However, one of the key challenges we now face is uncovering reliable means to construct ever more complex architectures, but with increased efficiency and predictability. This proposal is focused on the development of methodology that will allow chemists to harness transiently generated strained intermediates, such as arynes, heterocyclic alkynes, and heterocyclic allenes, in order to efficiently build complex molecular scaffolds. More specifically, we propose an enamine arylation/alkenylation reaction to establish quaternary stereocenters, in addition to three component couplings, which should allow for the formation of up to two new bonds and two sp3 centers. Next, the use of uncommon and highly reactive heterocyclic allenes to assemble complex architectures through the introduction of up to two new bonds and three sp3 centers is described. Preliminary results demonstrate the feasibility of the proposed methodologies. In the final section, we propose a concise and ambitious total synthesis of acantholactone, a member of the manzamine family of alkaloids that has yet to be synthesized. The results of our studies should lead to powerful new strategies and tools for accessing various molecules of importance, including natural products and medicines.